Challenges in the Management of Juvenile Myelomonocytic Leukaemia in Hong Kong Over the Past Two Decades
Juvenile myelomonocytic leukaemia (JMML) is a rare myeloid malignancy of childhood. The diagnosis and treatment of this disease still remain as major clinical challenges. We aim to describe the clinical and pathological findings, as well as treatment outcomes of eight patients with JMML who received treatment in two hospitals in Hong Kong between 1993 and 2011. One patient with Noonan syndrome showed spontaneous resolution of disease. Four patients underwent allogeneic haematopoietic stem cell transplantation during 1996 to 2007. Three of them died of post-transplant relapse and refractory disease or transplant-related toxicity. The surviving transplanted patient had chronic graft-versus-host disease for 4 years, and eventually showed evidence of disease relapse with documented mixed chimerism. The other three patients who received supportive treatment were alive with persistent disease. Our future works should focus on optimising therapy and improving treatment outcome for JMML patients.
Keyword : Case series; Diagnosis; Juvenile myelomonocytic leukaemia; Treatment outcome
Juvenile myelomonocytic leukaemia (JMML) is an aggressive clonal disorder of childhood. It accounts for 2-3% of all pediatric hematologic malignancies.1,2 The World Health Organization Classification classifies JMML as a myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in children.3,4 This category currently encompasses most cases formerly diagnosed as juvenile chronic myeloid leukaemia (JCML), chronic myelomonocytic leukaemia (CMML) of infancy and infantile monosomy 7 syndrome. The median age at presentation is two years.5,6 Typical presenting features include constitutional symptoms (e.g., malaise, pallor, and fever), organomegaly and a high circulating white blood cell (WBC) count with peripheral monocytosis and circulating myeloid precursor cells. These are non-specific findings that can be seen transiently in bacterial or viral infections in young children.7-9 And sometime it may have to differentiate from myeloid leukaemia with low blast counts as well.10 The diagnostic criteria of the International JMML Working Group have been widely adopted.11 They include sophisticated investigations such as cytogenetics and in-vitro culture. These are either non-specific or the special technique is not widely available. Based on the advances in understanding of the molecular pathogenesis of JMML involving the deregulation of the Ras/MAPK signaling pathway, alternative diagnostic criteria were proposed. These incorporate NF1, RAS, and PTPN11 mutational status or presence of monosomy 7 into the diagnostic categories.12
Although the diagnosis of JMML has been refined, challenges continue to exist in therapy and prognostication. The probability of survival without allogeneic haematopoietic stem cell transplantation (HSCT) is less than 10%.5 While the current standard of care is HSCT, the results of the most recent trials showed an event-free survival of only 50%, with an unacceptably high relapse rate.13-15 In a few patients, clinical resolution and long-term survival was described in the absence of therapy.5,16 Moreover, the correlation between mutational status and clinical outcome remains controversial. We present here the first case series of JMML patients treated in Hong Kong over the past two decades, and highlight the need for further studies to formulate an evidence-based treatment strategy to manage this disease which currently has a very dismal prognosis.
All paediatric JMML patients treated in Queen Mary Hospital (QMH) and Tuen Mun Hospital (TMH) between 1993 and 2011 were recruited from clinical databases. Socio-demographic, clinical and laboratory characteristics, treatment and outcome of the patients were collected from review of medical records. Accrued data were analyzed using descriptive statistics. The length of follow-up was calculated from the date of diagnosis until the last clinical information on the patient up to October 2011.
We identified eight patients with a diagnosis of JMML treated in our two institutes over an 18-year period (1993-2011), with a median follow-up time of 24 months (range, 5 to 53 months). Table 1 shows their epidemiological and clinical and laboratory features at diagnosis. The median age at diagnosis was 2.3 years (range, 9 months to 11 years); with a male-to-female ratio of 3:1. Seven patients were Chinese and one was an Indonesian. Three patients (Patient 1, 4, and 5) presented first to QMH and TMH, while the remaining five were referred from other hospitals and had received prior treatment.
Clinical Features and Basic Laboratory Findings
Fever was the most common symptom, present in 75%, followed by bleeding (37%) and diarrhoea (37%). Salmonella sepsis was documented in one patient (Patient 3) at diagnosis. One patient (Patient 7) presented with coexistent cytomegalovirus (CMV) infection. The median presenting WBC and absolute monocyte count were 23.6x109/L (range, 12.5 to 89.1x109/L) and 4.6x109/L (range, 0.9 to 10.7x109/L), respectively. The median haemoglobin concentration was 10.4 g/L (range, 8.3 to 11.5 g/dL). The median platelet count was 77x109/L (range, 30 to 145x109/L). As shown in Figure 1, peripheral blood smear of patients typically demonstrated leukocytosis and monocytosis with a leucoerythroblastic blood picture. Hypercellularity with active granulopoiesis were noted in all marrow specimens. Mild to moderate degree of dysplastic features were also found in marrow cells in three patients. The median blast count in peripheral blood and bone marrow was 6% (range, 3 to 24%) and 5% (range, 2 to 18%), respectively. Three of eight patients presented with an elevated fetal haemoglobin (HbF) level for age.
Genetic Study Results
Cytogenetic analysis demonstrated monosomy 7 in three patients. Multiple monosomies were seen in one patient. Addition of chromosomal material at 8q24.3 was found in two patients. Two patients had underlying neurofibromatosis type 1 (NF1) with a strong family history. One patient had Noonan syndrome (NS) with identified mutation in PTPN11, whereas another patient had PTPN11 mutation detected at diagnosis of JMML with undetected clinical phenotypes of NS. In-vitro hypersensitivity to granulocyte-macrophage colony stimulating factor (GM-CSF) was observed in one patient where it was examined. Overall, all patients were compatible with diagnosis of JMML based on current WHO criteria17 and the updated diagnostic criteria.12
Treatment and Outcome
Patients received different types of therapy, ranging from supportive care to intensive chemotherapy. Patient 6 received 13-cis retinoic acid therapy only. Treatment with intensive chemotherapy resulted in transient clinical improvements in Patient 2 and 8, who presented with hyperleukocytosis with excess blasts in peripheral blood. Complete remission could not be induced in any of those receiving chemotherapy.
Four of eight patients (Patient 1 to 4) underwent allogeneic HSCT during 1996 to 2007. Regarding the other four non-transplant patients, they were treated with supportive treatment while watchful waiting for appropriate donor identification. The median time from first admission in QMH to the first HSCT was 5.8 months (range, 5-8 months). Splenectomy/splenic irradiation before transplantation was performed in all patients, either prior to the first or second HSCT. Only Patient 1 received an HLA identical sibling transplant. Patient 2, 3, and 4 were recipients of HLA mismatched (for 1 to 2 out of 6 HLA antigens) related or unrelated transplants. Patient 1 had haematological relapse at 2 months after peripheral blood stem cell transplantation (PBSCT). A second HSCT was performed using bone marrow stem cells from the same donor. Subsequently, he died of disease progression at 3 months post-second HSCT. Patient 3 relapsed at eleven months after the first HSCT. She received donor lymphocyte infusions (DLI). However, she expired from disease progression at 3 months after DLI. Patient 2 developed primary engraftment failure, and subsequently received a second transplant with half-brother donor. Unfortunately, the disease was complicated with secondary acute respiratory distress syndrome immediately after stem cell infusion and he succumbed one week later to septicaemia. These three patients died of refractory disease or transplant-related toxicity at a median of 24 months after first diagnosis (range, 13 to 77 months). Patients 4 had refractory chronic graft-versus-host disease (cGVHD) of oral cavity and gastrointestinal tract 4 years after engraftment. Recently, he developed autoimmune haemolytic anaemia, raised WBC with monocytosis. Genetic monitoring showed a stable mixed chimerism (approximately 30% donor cells). His cGVHD status and other clinical conditions remained stable while receiving supportive treatment. In the four patients (Patient 5 to 8) who did not receive HSCT, one patient (Patient 5) with NS, who presented with a JMML-like MPN in the infantile period, had spontaneously resolution of haematological abnormalities at 5 years of age. The other three non-transplant patients were alive with disease. The treatment and outcome of this patient cohort are summarised in Table 2.
Unlike commonly seen in other myeloid malignancies of childhood, JMML is a rare mixed MDS/MPN of young children with a high mortality rate. The estimated incidence of childhood MDS among Chinese children was estimated to be 2.1/million children/year and JMML accounts for around half of the childhood MDS.18 A local review of 21 JMML cases reported in the recent two decades (1993-2010) does support the rarity of this disease in Hong Kong (Chan GCF, unpublished data). JMML usually manifests with nonspecific symptoms that are common to infectious diseases and other haematologic malignancies. JMML is known to mimic viral infections, including CMV, Epstein-Barr virus (EBV), human herpesvirus (HHV)-6, and parvovirus B19 infection.19-24 Hypersensitivity to GM-CSF, which is a hallmark of JMML, has also been reported in isolated cases of CMV and HHV-6 infection.21,23 Two patients from our case series, however, presented with concomitant JMML and infection. Combination of microbiological and histopathological investigations is extremely important for differential diagnosis. Absence of significantly elevated HbF and dysplastic features in marrow cells may also help to differentiate benign from malignant diseases.
The discovery of somatic and germ-line mutations encoding proteins in the Ras/MAPK signaling pathway have improved the diagnostic specificity for JMML. The recent proposed diagnostic criteria suggest combining genetic and morphological findings for diagnosis of JMML.12 However, molecular diagnostic tools are still not routinely available. Only two patients from our series had been studied for PTPN11 mutation, which is known to be mainly associated with NS.25 In non-NS patients with JMML, PTPN11 somatic missense mutations still represent the most frequent group of molecular lesions.26 Patient 3 in this series carried a constitutional PTPN11 215C>T (Ala72Val) mutation which has been previously documented in de novo, non-syndromic JMML.27-29 This patient presented at age of 1.5 years with fever, bleeding and hepatosplenomegaly. She received supportive treatment before proceeding to a mismatched related donor HSCT at 6 years of age because of disease progression. Eventually, she died of disease relapse at 15 months after HSCT. Another patient (Patient 5) was diagnosed with NS in infantile period. The diagnosis was based on clinical characteristics, including typical facial features, pectus carinatum, a height below the third percentile for age and cryptorchidism.30,31 A known NS-associated PTPN11 (218C>T, Thr73Ile) mutation was identified, which commonly predisposes to self-resolving JMML.27-29 He also developed JMML at 2 years of age. Cytogenetic study of marrow cells showed an acquired abnormality of 8q [46,XY,add(8)(q24.3)]. Spontaneous remission occurred at 5 years of age. A recent marrow study in early 2011 showed granulocytic hyperplasia only, with a normal karyotype. These contrasting clinical courses in our two PTPN11-mutated patients suggest that the background of a PTPN11 mutation (NS or non-NS) and/or its nature (specific amino acid substitution) may affect disease outcome and thus rational treatment in individuals. In non-NS patients, a phenomenon of 'self-resolving' JMML has been reported in patients with various homozygous CBL mutations and RAS mutations.32-34 However, the exact prognostic significance of common specific mutations in JMML (NF1, RAS, PTPN11, CBL) remains to be elucidated in a large population. Collaborative studies of comprehensive genetic analysis in JMML are required to shed light on potential risk-adapted and advance targeted therapeutic interventions.
To formulate the treatment approaches in JMML is always challenging, especially in the absence of tractable molecular markers. According to dismal outcome for non-transplant approaches in the previous decade,5 we proceeded to HSCT for patients who had been identified those HLA-compatible donors in the period of 1996-2007. Pre-transplant splenectomy was performed in our selected patients. The conditioning regimen published by the EWOG-MDS35 was applied, which consists of busulfan, cyclophosphamide, melphalan for first transplants, and addition of total body irradiation (TBI) for second transplants. However, these previous transplant approaches are currently uncertain in terms of efficacy and impact on ultimate outcome. The second HSCT and DLI which was shown to facilitate disease remission in several studies35-39 could not restore complete remission in our patients. This study illustrates that relapse is the major cause of treatment failure in JMML patients undergoing HSCT, and disease progression is the most frequent cause of death. Only one transplant survivor who has been suffering from protracted cGVHD, also suggests the importance of a graft-versus-leukaemia (GVL). This creates a management dilemma because aggressive immunosuppressive therapy may abolish the GVL effect, resulting in relapse. To control GVHD while maintaining GVL is critically essential for a durable remission. Advance transplant strategies, including the generation of GVL effect in JMML by reduced-intensity conditioning, inhibitory killer cell immunoglobulin-like receptor (KIR) ligand incompatibility40-42 are being thoroughly investigated.
JMML is a hybrid MDS/MPN of early childhood. Although advances have been made in its pathogenesis, JMML remains as one of the most difficult paediatric myeloid malignancies to treat. Widely accessible genetic analysis may facilitate diagnosis and provide further insights into genotype-phenotype correlation and prognostication of JMML. Studies to improve treatment outcome, in particular to minimise relapse rate, are urgently needed. International collaboration will be necessary to manage this rare but challenging disease.
We are indebted to all clinical staff members at QMH, TMH and referral hospitals who cared for these patients. Those patients and families who took part in this study are highly appreciated for their contribution.
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